CATABOLISM OF BRANCED CHAIN AMINO ACIDS Valine Leucine
CATABOLISM OF BRANCED CHAIN AMINO ACIDS ( Valine , Leucine, Isoleucine ) MAPLE SYRUP URINE DISEASE MSUD
The branched chain amino acids, isoleucine, and valine, are essential amino acids. In contrast to other amino acids, they are metabolized primarily by the peripheral tissues (particularly muscle, brain, kidney and adipose tissue), rather than by the liver. Because these three amino acids have a similar route of catabolism, it is convenient to describe them as a group
MAPLE SYRUP URINE DISEASE An inherited deficiency of branched-chain á-keto acid dehydrogenase results in accumulation of the branched chain á keto acid substrates in the urine. Their sweet odor prompted the name maple syrup urine disease
When the branched chain amino acids valine, isoleucine, and leucine are degraded in extra-hepatic tissues they share two common enzymes: 1. branched-chain aminotransferase and 2. branched-chain á-ketoacid dehydrogenase complex
Maple syrup urine disease (MSUD) is a rare (1: 185, 000), autosomal recessive disorder in which there is a partial or complete deficiency in branched-chain á-keto acid dehydrogenase, that decarboxylates leucine, isoleucine, and valine. These amino acids and their corresponding á keto acids accumulate in the blood, causing a toxic effect that interferes with brain functions.
Transamination: Removal of the amino groups of all three amino acids is catalyzed by a single, vitamin B 6–requiring enzyme, branched-chain amino acid aminotransferase
Oxidative decarboxylation: Removal of the carboxyl group of the á keto acids derived from leucine, valine, and isoleucine is catalyzed by a single multienzyme complex, branched-chain á-keto acid dehydrogenase complex. This complex uses thiamine pyro phosphate, lipoic acid, FAD, NAD+, and Co. A as its coenzymes.
END PRODUCTS: The catabolism of isoleucine ultimately yields acetyl Co. A and succinyl Co. A, rendering it both ketogenic and glucogenic. Valine yields succinyl Co. A and is glucogenic. Leucine is ketogenic, being metabolized to acetoacetate and acetyl Co. A.
[Note: Branched chain amino acid catabolism also results in glutamine and alanine being sent out into the blood from muscle. ]
FAD linked Dehydrogenation: Oxidation of the products formed in the above reaction yields á unsaturated acyl Co. A derivatives. [Note: Deficiency in the dehydrogenase specific for isovaleryl Co. A causes neurological problems, and is associated with a “sweaty feet” odor in body fluids. ]
Maple Syrup Urine Disease • Types: – Classic type: Most common, due to little or no activity of a-ketoacid dehydrogenase – Intermediate and intermittent forms: Some enzyme activity, symptoms are milder – Thiamin-responsive form: High doses of thiamin increases a-ketoacid dehydrogenase activity
The disease is characterized by feeding problems, vomiting, dehydration. The levels of branched chain amino acids and corresponding ketoacids are markedly elevated in both blood and urine. The urine has the odor of maple syrup The early symptoms: § lethargy § mental and physical retardation §ketoacidosis §unrecognized disease leads to seizures, coma, and death
Infants with classic MSUD show symptoms within the first several days of life. If not diagnosed and treated, classic MSUD is lethal in the first weeks of life.
Patients with intermediate forms have a higher level of enzyme activity (approximately 3– 15% of normal). The symptoms are milder and show an onset from infancy to adulthood. Patients with the rare thiamine dependent variant of MSUD achieve increased activity of branched chain áketo acid dehydrogenase if given large doses of this vitamin
The urine has the odor of maple syrup or burnt sugar
DIAGNOSIS Diagnosis is made by: 1. Finding elevated concentrations of all branched chain amino acids in plasma and less reliably in urine. 2. Finding characteristic keto acids in urine by organic acid GCMS (Gas Chromatography Mass Spectrometry) analysis can also be helpful.
TREATMENT: The disease is treated with a synthetic formula that contains limited amounts of leucine, isoleucine, and valine—sufficient to provide the branched chain amino acids necessary for normal growth and development without producing toxic levels. Early diagnosis and lifelong dietary treatment is essential if the child with MSUD is to develop normally.
MAPLE SYRUP URINE DISEASE ………. . SUMMARY A common enzyme catalyses the oxidative decarboxylation of the ketoacids derived from the deamination of leucine, isoleucine and valine. Deficiency of this enzyme causes maple syrup urine disease. The urine has a heavy, sickly odour but more importantly the affected children suffer from fluctuating but progressive neurological disease. The severity of the encephalopathy is directly related to the plasma concentration of leucine which needs to be carefully monitored. Children with MSUD are also at risk of metabolic crises. These often follow a catabolic event and can present with metabolic acidosis and sometimes hypoglycaemia. Diagnosis is made by finding elevated concentrations of all branched chain amino acids in plasma and less reliably in urine together with the presence of the unusual amino acid alloisoleucine. Finding characteristic keto acids in urine by organic acid GCMS analysis can also be helpful. Treatment consists of a diet low in branched chain amino acids. Emergency procedures to stimulate anabolism, and even haemodialysis, are necessary during acute episodes.
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